Hypotensive compositions containing 2-(2&#39; - halo-anilino) - 1,3 -diazacyclopentenes-(2) and methods of using the same

ABSTRACT

HYPOTENSIVE COMPOSITIONS COMPRISING A DERIVATIVE OF 2(2&#39;&#39;-HALO-ANILINO)-1,3-DIAZACYCLOPENTENE-(2) AS AN ACTIVE INGREDIENT, AND A METHOD OF REDUCING THE BLOOD PRESSURE IN WARM-BLOODED ANIMALS THEREWITH.

United States Patent HYPOTENSIVE COMPOSITIONS CONTAINING 2- (2'HALO-ANILINO) 1,3 DIAZACYCLOPEN- TENES-(2) AND METHODS OF USING THE SAMEHelmut Stable, Herbert Kiippe, Karl Zeile, and Martin Wolf, Ingelheim amRhein, and Wolfgang Hoefke, Budenheim (Rhine), Germany, assignors toBoehringer Ingelheim G.m.b.H., Ingelheim am Rhein, Germany No Drawing.Original application Sept. 30, 1966, Ser. No. 583,421, now Patent No.3,462,433, dated Aug. 9, 1969. Divided and this application Apr. 17,1969, Ser. No.

817,200 Claims priority, applicatison9germany, Oct. 1, 1965, 3

Int. Cl. A61k /12 US. Cl. 424-273 14 Claims ABSTRACT OF THE DISCLOSUREHypotensive compositions comprising a deriative of 2-(2'-halo-anilino)-1,3-diazacyclopentene-(2) as an active ingredient, anda method of reducing the blood pressure in warm-blooded animalstherewith.

This is a division of copending application Ser. No. 583,421, filedSept. 30, 1966, nowU.S. Pat. No. 3,462,433.

The present invention relates to hypotensive compositions comprising asan active hypotensive ingredient a novel derivative of 2(2-halo-anilino)-1,3-diazacyclopentene-(Z), as Well as to a method ofreducing the blood pressure in warm-blooded animals therewith.

More particularly, the present invention relates to hypotensivecompositions comprising as an active hypotensive ingredient a member ofa novel class of 2-'(2'- haloanilino)-1,3-diazacyclopentenes-(2) of theformula wherein R is chlorine, bromine or fluorine, and R is bromine,fluorine, 3-, 4-, or S-trifluoromethyl, 4-

cyano, or 3- or S-chloro,

l NH

R SR (II) wherein R and R have the same meanings as in Formula =1, R islower alkyl, and X is the anion of an acid, preferably the anion of ahydrohalic acid, with ethylenediamine The reaction may be carried outwith or without an inert solvent. Thus, the reaction may be effected bysimply heating a mixture of the reactants to between 100 and ice 200 0.,whereby satisfactory yields of the desired end product are obtained.Alternatively, the reaction may also be carried out at relatively lowtemperatures (60-140" C.) in the presence of a suitable inert solvent,preferably one which contains polar groups, such as water or a loweralkanol; however, under these conditions longer reaction periods must beaccepted if good yields are to be achieved.

The isothiouronium salt of the Formula II may itself be prepared bycustomary methods, such as by heating a thiourea derivative of the'Formula III below, obtained from a correspondingly substituted anilineand ammonium thiocyanate (Houben Weyl, vol. 9, p. 887), with analkylating agent, such as a lower alkyl halide or a di-loweralkylsulfate.

Method B.By reacting an N-phenyl-thiourea compound of the formula CH NHC'HFHM R1 (IV) wherein R and R have the same meanings as in Formula 1and Y is oxygen or sulfur, to pyrolysis to effect ring closure of thediazacyclopentene ring.

A starting compound of the Formula IV may itself be obtained by reactinga corresponding substituted phenylisocyanate or phenyl-isothiocyanatewith ethylenediamine, pursuant to the method described in Journal ofOrganic Chemistry, vol. 24, page 818 (1959).

The end products obtained by Methods A through C, that is, the compoundsembraced by Formula I, are organic bases and form non-toxic salts,especially non-toxic, pharmacologically acceptable acid addition salts,with various inorganic or organic acids and synthetic acid resins.Examples of non-toxic, pharmacologically acceptable acid addition saltsinclude, but are not limited to, those formed with hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, oxalicacid, 8 chlorotheophylline or the like. An example of a non-toxic saltwith an acid synthetic resin is that formed with a crosslinkedpolystyrene polymer containing sulfonic acid groups, such as Zeo-Karb225 (manufactured by The Permutit Co., New York).

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. -Itshould be understood, however, that the invention is not limited to theparticular examples given below.

EXAMPLE 1 Preparation of 2-(2'-chloro-5'-trifluoromethyl-anilino)-1,3-diazacyclopentene-(2) by method A A mixture of 15.8 gm. (0.04 mol)of N-(Z-chloro-S-trifiuoromethyl-phenyl)-isothiouronium hydroiodide, 4cc. of ethylenediamine of the stoichiometrically required amount) and 50cc. of methanol was refluxed for 24 hours. Thereafter, the methanol andthe excess unreacted ethylenediamine were distilled 01f in vacuo, theresidue was taken up in 20 cc. of methanol, and the resulting solutionwas made alkaline with 30 cc. of aqueous 30% potassium hydroxide. Theinitially oily precipitate formed thereby became crystalline aftercooling the reaction mixture with ice; it was isolated by vacuumfiltration, washed with water and dried. gm. (47.6% of theory) of 2-(2-chloro 5 -trifluoromethyl-anilino)-1,3-diazacyclopentene- (2), M.P.l2l-123 C., of the formula were obtained.

EXAMPLE 2 Preparation of2-(2-chloro-4-fluoro-anilino)-1,3-diazacycylopentene-(2) by method A Amixture of 27.7 gm. (0.09 mol) of N-(2-chloro-4-fiuoro-phenyl)-isothiouronium hydroiodide and 8 cc. of ethylenediamine(150% of the stoichiometrically required amount) was heated, without asolvent, to 140 C. and was maintained at that temperature for 45minutes. Thereafter, the excess unreacted ethylenediamine was evaporatedin vacuo, the residue was taken up in dilute aqueous hydrochloric acidat about 70 C., and the solution was made alkaline with 5 N sodiumhydroxide. The initially oily precipitate formed thereby becamecrystalline after cooling the reaction mixture With ice; it wasseparated by vacuum filtration, washed with water and with petroleumether at 40 0., and recrystallized from benzene/petroleum ether. 5.2 gm.(29.7% of theory) of pure 2-(2'-chloro-4'-fluoro-anilino)-1,3-diazacyclopentene-(2), M .P. 132132.5 C.,of the formula I I? H were obtained.

Its hydrochloride, obtained by acidifying an ethereal solution of thefree base with ethereal hydrochloric acid, had a melting point of 161163C., was freely soluble in water, and was thin-layer chromatographicallypure.

EXAMPLE 3 Using a procedure analogous to that described in Example 1,2-(2'-chloro-4'-trifiuoromethyl-anilino)-1,3- diazacyclopentene-(Z),M.P. 112 C., was prepared from N (2chloro-4-trifiuoromethyl-phenyl)-isothiouronium hydroiodide andethylenediamine. The yield was 15.4% of theory.

Its nitrate had a melting point of 138140 C.

EXAMPLE 4 Preparation of2-(2'-chloro-4-bromo-anilino)-1,3-diazacyclopentene-(2) by method A Amixture of 24.3 gm. (0.1 mol) of 2-chloro-4-bromoaniline hydrochloride,8 gm. (0.105 mol) of ammonium thiocyanate and 130 cc. of chlorobenzenewas heated for about ten hours at 95-100 C. Thereafter, the reactionmixture was cooled, the precipitate formed thereby was collected byvacuum filtration, washed with water and petroleum ether, digested with200 cc. of Water, 200 cc. of petroleum ether were added, the mixture wasmade alkaline with sodium carbonate, and the precipitate was separatedby vacuum filtration. 26.54 gm. (0.1 mol) of N-(2-chloro-4-bromo-phenyl)-isothiourea were obtained, which were admixedwith 100 cc. of methanol and 21.3 gm. (0.15 mol) of methyliodide, andthe mixture was boiled for 1.5 hours. Thereafter, the reaction mixturewas evaporated in vacuo, and the residue was dried. 40.7 gm. (0.1 mol)of N-(2-chloro-4-bromo-phenyl)-isothiouronium hydroiodide were obtained.This product was admixed wtih 70 cc. of methanol and 9 gm. (0.15 mol) ofethylenediamine, and the mixture was refluxed for 16 hours. Thereafter,the methanol was distilled 01f in vacuo, the residue was dissolved in asmall amount of methanol, and the solution was made alkaline withaqueous 50% potassium hydroxide, cooled and then vigorously stirred withpetroleum ether. The insoluble matter was separated by vacuumfiltration, washed with water, dried and recrystallized frombenzene/petroleum ether, yielding 2-(2-chloro-4-bromo-anilino)-1,3-diazacyclopentene- (2) M.P.

142-145 C. of the formula This free base product was dissolved in ether,the solution was acidified with ethereal hydrochloric acid, and theprecipitate formed thereby was recrystallized from methanol/ether,yielding thin-layer-chromatographically pure 2- (2'chloro-4-bromo-anilino)-l,3-diazacyclopentene-(2) hydrochloride, M.P.203-205 C.

EXAMPLE 5 Using a procedure analogous to that described in Ex ample 4,2-(2'-bromo-5'-chloro-anilino)-1,3-diazacyclopentene-(Z), M.P. 172-173C., of the formula N I N] 01 was prepared fromN-(2-bromo-5-chloro-phenyl)-isothiouronium hydroiodide andethylenediamine.

Its thin-layer-chromatographically pure hydrochloride had a meltingpoint of 255-256" C.

EXAMPLE 6 Preparation of2-(2-chloro-5'-bromo-anilino)-1,3-diazacyclopentene-(2) by method A 129gm, (0.75 mol) of 4-chloro-aniline were subjected to the SandmeyerReaction with CuBr, yielding 165 gm. (93.5% of theory) of2-chloro-S-bromo-nitrobenzene. The product was hydrogenated under normalconditions of temperature and pressure in the presence of Raney nickelas a catalyst until the calculated amount of hydrogen had been absorbed,yielding of theory of 2-chloro-5-bromo-aniline, whose hydrochloride hada melting point of 190193 C.

24.3 gm. (0.1 mol) of 2-chloro-5-bromo-aniline hydrochloride wereadmixed with 8 gm. (0.105 mol) of ammonium thiocyanate and 130 cc. ofchlorobenzene, and the mixture was heated at 95100 C. for about eighthours. Thereafter, the reaction mixture was cooled, and the precipitatewas collected by vacuum filtration, washed with water and petroleumether, digested with 200 cc. of Water, 200 cc. of petroleum ether wereadded, the solution was made alkaline with sodium carbonate, and theprecipitate formed thereby Was collected by vacuum filtration. 41.4% oftheory of N-(2-chloro-5-bromo-phenyl)- isothiourea, M.P. 131133 C., wereobtained.

11 gm. (0.041 mol) of N-(2-chloro-5-bromo-phenyl)- isothiourea wereadmixed with 40 cc. of methanol and 3.8 cc. of methyliodide, and themixture was boiled for 1.5 hours. Thereafter, the reaction solution wasevaporated, and the residue was dried. TheN-(2-chloro-5-bromophenyl)-isothiouronium hydroiodide thus obtained wasadmixed with 40 cc. of methanol and 4.1 cc. of ethylenediamine of thestoichiometrically required amount), and the mixture was refluxed for 17hours.

Thereafter, the methanol and the unreacted excess ethylenediamine weredistilled off in vacuo, the residue was dissolved in a small amount ofmethanol, and the solution was made alkaline with aqueous 50% potassiumhydroxide, cooled and then vigorously stirred with petroleum ether. Theprecipitate was collected by vacuum filtration, washed with water anddried. 6.0 gm. (53.0% of theory) of2-(2-chloro-5'-bromo-anilino)-1,3-diazacyclopentene- 2). MP. 157160 C.,of the formula were obtained.

Its thin-layer-chromatographically pure hydrochloride had a meltingpoint of 251253 C.

Analysis (hydrochloride).Calculated (percent): C, 34.75; H, 3.24; N,1351; C1, 22.79; Br, 25.69. Found (percent): C, 34.58; H, 3.39; N,13.32; Cl, 22.98; Br, 25.65.

EXAMPLE 7 Using a procedure analogous to that described in Example 6-, 2(2',5 difluoro-anilino)-1,3-diazacyclopentene- (2), M.P. 138-141 C., ofthe formula was prepared starting from 2,5-difluoro-anilinehydrochloride through the intermediates N-(2,5-difluoro-phenyl)-isothiourea, M.P. 203 C., and N-(Z-S-difluoro-phenyl)-S-methylisothiouronium hydroiodide. The yield was 19.6% of theory.

Its thin-layer-chromatographically pure hydrochloride had a meltingpoint of 205-206 C.

EXAMPLE 8 Using a procedure analogous to that described in Example, 6,2-(2',4'-difluoro-anilino)-1,3-diazacyclopentene- (2), MP. 123-126 C.after recrystallization from a mixture of benzene and petroleum etherhaving a boiling point from 40-80 C., was prepared starting from 2,4-difluoro-aniline hydrochloride.

Its nitrate, obtained by dissolving the free base in ether andacidifying the solution with concentrated nitric acid until it reactedacted to Congo red, was thin-layer-chromatographically pure and had amelting point of 121- 121.5" C. after recrystallization from a mixtureof methanol and ether.

EXAMPLE 9 Preparation of 2-(2'-bromo-5'-trifluoromethy1-anilino)-1,3-diazacyclopentene-(2) by method A A mixture of 8.3 gm. (0.028 mol)of N-(2-bromo-5- trifluoromethyl-phenyl)-isothiourea, 2.5 cc. ofmethyliodide and 30 cc. of methanol was boiled for two hours, yielding N(2 bromo trifiuoromethyl phenyl) S- methylisothiouronium hydroiodide.This product was admixed with 2.8 cc. of ethylenediamine and 30 cc. ofmeth anol, and the mixture was refluxed for 16 hours. Thereafter, themethanol and the excess unreacted ethylenediamine were distilled oif invacuo, the residue was taken up in a small amount of methanol, and thesolution was made alkaline with aqueous 50% potassium hydroxide. Theinitially oily precipitate formed thereby was made to cyclopentene-(Z)was prepared from N-(2-chloro-3-triand was then filtered off, washedwith water and dried. 6.0

gm. (69.5% of theory) of2-(2'-bromo-5'-trifiuoromethylanilino)-1,3-diazacyclopentene-(2), M.P.144-145 C. after recrystallization from benzene/petroleum ether, of theformula I N a l Were obtained.

Its nitrate had a melting point of 161162 C.

EXAMPLE 10 Using a procedure analogous to that described in Example 1,2-(2-chloro-3-fluoro-anilino)-l,3-diazacyclopentene-(2) was preparedfrom N-(2-chloro-3-fluorophenyl)- S-methyl-isothiouronium hydroiodideand ethylenediamine.

EXAMPLE 11 Using a procedure analogous to that described in EX- ample 1,2-(2'-chloro-5-fluoro-anilino)-l,3-diazacyclo pentene-(Z) was preparedfrom N-(2-chloro-5-fiuorophenyl)-S-methyl-isothiouronium hydroiodide andethylenediamine.

EXAMPLE 12 Using a procedure analogous to that described in Example 1,2-(2'-chloro-3-bromo-anilino)-1,3-diazacyclopentene-(2) was preparedfrom N-(2-chloro-3-bromophenyl)-S-methyl-isothiouronium hydroiodide andethylenediamine.

EXAMPLE 13 Using a procedure analogous to that described in Example 1,2-(2'-chloro-3'-trifluoromethyl-anilino)-l,3-diazacyclopentene-(Z) wasprepared from N-(2-chloro-3-tri fluoromethyl-phenyl) Smethyl-isothiouronium hydroiodide and ethylenediamine.

EXAMPLE 14 Using a procedure analogous to that described in Example 1,2-(2-bromo-3-fiuoro-anilino)-1,3-diazacyclopentene-(2) was prepared fromN-(2-bromo-3-fluorophenyl)-S-methyl-isothiouronium hydroiodide andethylenediamine.

EXAMPLE 15 Using a procedure analogous to that described in Example 1,2-(2'-bromo-4-fluoro-anilino) 1,3 diazacyclopentene-(Z) :was preparedfrom N-(2-bromo-4-fluorophenyl)-S-isothiouronium hydroiodide andethylenediamine.

EXAMPLE 16 Using a procedure analogous to that described in Ex ample 1,2 (2-brorno-3'-trifluoromethyl-anilino)-l,3-diazacyclopentene-(Z) wasprepared from N-(2-bromo-3- trifluoromethyl-phenyl)-S-methylisothiouronium hydroiodide and ethylenediamine.

EXAMPLE 18 Using a procedure analogous to that described in Example 1,2- (2-bromo-4-trifluoromethyl-anilino)-1,3-diazacyclopentene-(Z) wasprepared from N-(2-bromo-4- trifiuoromethyl-phenyl)-S-methy1isothiouronium hydroiodide and ethylenediamine.

EXAMPLE 19 Using a procedure analogous to that described in Example 1, 2(2'-chloro-4-cyano-anilino)-l,3-diazacyclopentene-(2) was prepared fromN-(2-chloro 4 cyanophenyl)-S-methyl-isothiouronium hydroiodide andethylenediamine.

The compounds embraced by Formula I above and their non-toxic,pharmacologically acceptable acid addition salts have usefulpharmacodynamic properties. More particularly, these compounds exhibithypotensive activities in warm-blooded animals; their advantage overknown compounds of similar structure is that the gastric juicesecretion-inhibiting side effect is substantially less pronounced thanin said related known compounds, as demonstrated by the followingcomparative tests.

The tests served for the determination of the influence of the testcompounds upon the gastric juice output of the stomach of rats pursuantto the method of Shay et al., Gastroenterology, vol. 5, page 43 1945).The tests were made on juvenile rats having a body weight of 100 to 150gm. For at least two days prior to the start of the tests the rats werefed only white bread, and during the last 24 hours they received onlydistilled water in order to empty the stomach. Ten rats per dose wereused.

The test compounds were injected subcutaneously at dosage levels of 10,3, 1, 0.3 and 0.1 mgm./kg. in physiological saline solution. The animalswere anesthetized with ether, and then an incision was made in theabdominal wall below the sternum along the linea alba. A ligature wasapplied around the pylorus. The abdominal muscles and the skin were thensuccessively carefully clamped or sutured. The animal was weighed, andthe corresponding dose of the compound to be tested was injected. Ineach test series two control animals were administered onlyphysiological saline solution.

After four hours the rats were killed with ether. The abdominal cavitywas opened, the cranial esophagus of the cardia was clamped oif, theesophagus and the duodenum were severed from the stomach, the stomachcontents were emptied into a graduated cylinder, and the volume wasrecorded. The stomach was then rinsed twice with distilled water, andthe rinses were added to the contents of the graduated cylinder. Thecontents of the cylinder wee then filtered into a small Erlenmeyerflask, the graduated cylinder, the funnel and the filter were rinsedwith distilled water, and the rinse water was added to the contents ofthe flask. About two drops of a mixed indicator (p dimethyl aminoazobenzene and phenolphthalein) were added to the contents of the flask,and the solution was titrated against 0.1 N sodium hydroxide. The firstend point, indicated by a color change from red to salmon, occurred atpH 2.9; the second end point, indicated by a color change from salmon toyellow, occurred at pH 4.0; and the third end point, indicated by acolor change from yellow to pink, occurred at pH 8.5. The consumption ofsodium hydroxide up to the first end point indicated the amount of freehydrochloric acid in the stomach contents. In order to determine theamount of bonded HCl, the median value of the second and third end pointwas calculated, from which the amount of free HCl was subtracted. Thetotal consumption of NaOH at the third end point was designated as thetotal acidity.

The ED -values shown in the following table were graphically determinedfrom the individual test dosages and represent the dose of the testcompound which produces a 50% reduction in the secreted gastric juicevolume or a 50% decrease in the total acidity, compared to the controls.The smaller the ED the greater the gastric juice secretion-inhibitingactivity of the particular compound. The last column in the table alsoshows the averge of the two ED values given.

TAB LE ED in mgm./kg.

Total acidity Average Gastric Compound volume Prior art: Netherlandsapplication No.

The hypotensive activity of the compounds embraced by Formula I aboveand their non-toxic acid addition salts was ascertained by directmeasurement of the blood pressure changes in the carotid artery ofrabbits after administration of the compounds.

The test method was carried out as follows: Bastard rabbits of bothsexes, with a body weight of about 2 to 3 kg., were first weighed andthen anesthetized with 0.75 gm./ kg. of urethane i.p.

The fur on the neck of the animals was removed, a longitudinal incision7 to 10 cm. long was made, and the trachea was exposed into which arespiration canula was tied in order to be able to apply artificialrespiration to the animal in an emergency. One of the two carotidarteries lying on both sides of the trachea was exposed, and the canulaof a manometer was tied into it. The jugular vein was exposed from thefatty tissue, and a canula, provided with a stopcock, was tied into itas a means for intravenous administration of the test compounds.

The body temperature of the animal was continuously measured rectallyand, if necessary, was maintained at 37 to 38 C. with a heating pad.

The compound under investigation was injected into the jugular vein atdosages of 0.01, 0.03, 0.1, 1 and 3 mgm./ kg. body weight in increasingas well as decreasing sequence, and the resulting blood pressure changeswere recorded. Between injections, a waiting period equal to double theperiod of eifective action was used before the next injection wasadministered. One compound was tested on each animal, and from 2 to 9tests per compound were performed.

All of the compounds embraced by Formula I and their non-toxic acidaddition salts were found to be effective hypotensives.

For pharmaceutical purposes the compounds of the Formula I or theirnon-toxic acid addition salts are administered to warm-blooded animalsperorally or parenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one eifective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective dosage unit of the compoundsof the Formula I or their non-toxic acid addition salts is from 0.00083to 0.50 mgm./kg. body weight. A dosage unit composition comprising acompound of the Formula I or a non-toxic acid addition salt thereof asan active ingredient may, if desired, also contain an effective unitdose of another pharmacodynamically active ingredient, such as asaluretic agent, i.e. a compound which promotes the discharge of saltthrough the urine.

The following examples illustrate a few dosage unit compositionsaccording to the present invention and represent the best modecontemplated of putting the invention to practical use. The parts areparts by weight unless otherwise specified.

9 EXAMPLE 20 Tablets The tablet composition was compounded from thefollowing ingredients:

Parts 2-(2'-bromo-5'-chloro-anilino) 1,3 diazacyclopentene-(2)hydrochloride 0.30 Lactose 53.00 Corn starch 31.60 Soluble starch 4.00Mangnesium stearate -1.00

Total 90.00

The individual ingredients were admixed with each other in a mannercustomary for manufacture of pharmaceutical tablets, and the mixture waspressed into 90 mgm.-tablets. Each tablet contained 0.3 mgm. of thediazacyclopentene compound and, when administered perorally to awarm-blooded animal of about 60 kg. body weight in need of suchtreatment, produced very good hypotensive efi'ects without appreciablyreducing the gastric juice secretion rate in the stomach.

EXAMPLE 21 Drop solution The solution was compounded from the followingingredients:

Parts 2-(2-chloro 4' fluoro anilino 1,3 diazacyclopentene-(2)hydrochloride 0.02 p-Hydroxy-benzoic acid methyl ester 0.07p-Hydroxy-benzoic acid propyl ester 0.03

Demineralized water, q.s. ad 100.00 parts by vol.

The individual ingredients were dissolved in a sutficient amount ofdemineralized water, the solution was diluted with additionaldemineralized water to the desired volume, and the finished solution wasfiltered. 1 cc. of solution (about 20 drops) contained 0.2 mgm. of thediazacyclopentene compound and, when administered perorally to awarm-blooded animal of about 60 kg. body weight in need of suchtreatment, produced very good hypotensive effects without appreciablyreducing the gastric juice secretion rate in the stomach.

EXAMPLE 22 Hypodermic solution The solution was compounded from thefollowing ingredients:

Parts 2-(2'-chloro-4'-trifluoromethylanilino) 1,3-diazaclopentene-(2)hydrochloride 0.75 Sodium chloride 18.00 Distilled water, q.s. ad2000.00 parts by vol.

10 EXAMPLE 23 Suppositories The suppository composition was compoundedfrom the following ingredients:

Cocoa butter, q.s. ad 1700.0 parts The cocoa butter was melted, theremaining ingredients were stirred into it, the mixture was homogenized,and the finished composition was poured into cooled suppository molds,each holding 1700 mgm. of the composition. Each suppository contained7.0 mgm. of the diazacyclopentene compound and, when administered by therectal route to a warm-blooded animal of about 60 kg. body weight inneed of such treatment, produced very good hypotensive effects withoutappreciably reducing the gastric juice secretion rate in the stomach.

Analogous results were obtained when an equal amount of any one of theother compounds embraced by Formula I above or a non-toxic acid additionsalt thereof was substituted for the particular diazacyclopentenecompounds in Examples 20 to 23. Likewise, the amount of activeingredient in these examples may be varied to achieve the dosage unitrange set forth above, and the amounts and nature of the inertpharmaceutical carrier ingredients may be varied to meet particularrequirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention.

We claim:

1. A hypotensive composition in dosage unit form consisting essentiallyof an inert pharmacetical carrier and an effective hypotensive amount ofa compound of a formula selected from the group consisting of R ischlorine or bromine and R is 3-, 4- or S-trifiuoromethyl, or anon-toxic, pharmacologically acceptable acid addition salt thereof.

2. The method of lowering the blood pressure of a warm-blooded animal inneed of such treatment, which comprises perorally or parenterallyadministering to said animal an effective hypotensive amount of acompound of a formula selected from the group consisting of and whereinR is chlorine or bromine and R is 3-, 4- or S-trifiuoromethyl, or anon-toxic, pharmacologically acceptable acid addition salt thereof.

3. A hypotensive composition in dosage unit-form according to claim 1,wherein said compound is 2-(2'- chloro-3-trifluoromethyl anilino) 1,3diazacyclopentene-(2) or a non-toxic, pharmacologically acceptable acidaddition salt thereof.

4. A hypotensive composition in dosage unit form according to claim .1,wherein said compound is 2-(2- chloro-4-trifiuoromethyl-anilino) 1,3-.diazacyclope n.-

tene-(2) or a non-toxic, pharmacologically acceptable acid addition saltthereof.

5. A hypotensive composition in dosage unit form according to claim 1,wherein said compound is 2-(2- chloro-5'-trifiuoromethyl-anilino) 1,3diazacyclopentene-(Z) or a non-toxic, pharmacologically acceptable acidaddition salt thereof.

6. A hypotensive composition in dosage unit form according to claim 1,wherein said compound is 2-(2'- bromo3-trifluoromethyl anilino) 1,3diazacyclopentone-(2) or a non-toxic, pharmacologically acceptable acidaddition salt thereof.

7. A hypotensive composition in dosage unit form according to claim 1,wherein said compound is 2-(2- bromo-4'-trifiuoromethyl anilino) 1,3diazacyclopentene-(2) or a non-toxic, pharmacologically acceptable acidaddition salt thereof.

8. A hypotensive composition in dosage unit form according to claim 1,wherein said compound is 2-(2'- bromo-5'-trifiuoromethyl anilino) 1,3diazacyclopentene-(2) or a non-toxic, pharmacologically acceptable acidaddition salt thereof.

9. The method according to claim 2, wherein said compound is2-(2'-chloro-3'-trifiuoromethyl-anilino)-1,3-diazacyclopentene-(2) or anon-toxic, pharmacologically acceptable acid addition salt thereof.

10. The method according to claim 2, wherein said compound is2-(2'-chloro-4-trifiuoromethyl-anilino)-1,3- diazacyclopentene-(Z) or anon-toxic, pharmacologically acceptable acid addition salt thereof.

11. The method according to claim 2, wherein said compound is2-(2'-chloro-5'-trifiuoromethyl-anilino)-1,3- diazacyclopentene-(2) or anon-toxic, pharmacologically acceptableacid addition salt thereof.

12. The method according to claim 2, wherein said compound is2-(2'-bromo-3-trifluoromethyl-anilino)-1,3- diazacyclopentene-(Z) or anon-toxic, pharmacologically acceptable acid addition salt thereof.

' 13. The method according to claim 2, wherein said compound is2-(2-bromo-4'-trifiuoromethyl-anilino)-1,3- diazacyclopentene-(2) or anon-toxic, pharmacologically acceptable acid addition salt thereof.

14. The method according to claim 2, wherein said compound is2-(2'-bromo-5'-trifluoromethyl-anilino)-1,3- diazacyclopentene-(2) or anon-toxic, pharmacologically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,190,802 6/1965 Zeile et al.260309.6

FOREIGN PATENTS 625,631 8/1961 Canada 260-3096 OTHER REFERENCESNetherlands application 6411516, April 1965.

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant ExaminerUS. Cl. X.R. 260309.6

(5/69) l ERTIFICA"E OF CORRECTION men: No. 595 9 Dated ly 7, 1971Inventor) HELMUT STHHLE, HERBERT KOPPE, KARL ZEILE, MARTIN woLF-woironmflosmifi It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

. ii "1 Column 5, line 74: cancel cyc1opentene-(2) was prepared fromN-(2-chloro-3-triand insert --crysta.l1ize by cooling the reactionmixture on an ice bath -l Column 7, line 47: "wee" should read --were--Column 10,1ine 12: in the first formula "B" should read --R1--;

' line 48: in the 2nd formule "0" should ,read "01 V Signed and sealed'this 28th day of March 1972.-

(SEAL). v

Attest:

EDWARD M.FLETCH5R,J'R, ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

